Anti-angiogenic effect of rapamycin in mouse oxygen-induced retinopathy is mediated through suppression of HIF-1alpha/VEGF pathway.

Hypoxia-inducible factor-1alpha (HIF-1α)-vascular endothelial growth factor (VEGF) pathway, a downstream of mammalian target of rapamycin (mTOR), plays a major role in the formation of pathological retinal angiogenesis. Rapamycin (RAPA), a highly specific inhibitor of mTOR, is widely used in cancer studies for its antiangiogenic activity. However, the inhibitory effects of RAPA on the HIF-1α-VEGF pathway in retinal tissues were rarely researched. The study aimed to investigate the efficacy and potential mechanisms of RAPA in inhibiting retinal neovascularization. Human umbilical vein endothelial cells (HUVECs) were treated with hypoxia and in the presence of different concentrations of RAPA. RAPA was injected intraperitoneally in oxygen-induced retinopathy (OIR) C57BL/6 mice from postnatal day 12 (P12) to P17. The proliferation of HUVECs, the protein and mRNA expressions of HIF-1α and VEGF were evaluated in HUVECs or OIR mice using MTT assay, ELISA, immunohistochemistry, Western-blot and real-time PCR. Histological methods were used to count blood vessel profiles in the inner retina. RAPA inhibited HUVECs proliferation and retinal neovascularization by reducing protein and mRNA expressions of HIF-1α and VEGF. RAPA suppresses hypoxia-induced HUVECs cell proliferation and pathological ocular angiogenesis through a mechanism linked to the targeting of HIF-1α/VEGF signaling.